N-(N-containing heteroaryl)methyl-substituted cyclic amines are useful as intermediates in the preparation of pharmacologically active substances or as pharmacologically active substances per se. U.S. Pat. No. 5,413,999, for example, discloses a wide range of 5-piperazin-1-ylpentaneamide derivatives that are HIV protease inhibitors useful for treating HIV infection and AIDS. Among the derivatives described in U.S. Pat. No. 5,413,999 are compounds having an azaarylmethyl group substituted at the 4-position of the piperazinyl moiety, including indinavir (Compound J in the patent) which is marketed by Merck under the tradename CRIXIVAN®. As another example, WO 01/38332 discloses γ-hydroxy-α-(phenylmethyl)-2-[((fluoroalkyl)amino)carbonyl]-1-piperazinepentanamide derivatives that are potent inhibitors of HIV protease including mutant forms thereof that are resistant to approved products such as indinavir.
The N-heteroarylmethyl-substituted cyclic amines can be obtained by reductive alkylation of the corresponding cyclic amine with the appropriate heteroaryl carbaldehyde precursor. WO 01/38332, for example, discloses the preparation of 4-[(heteroaryl)methyl]-γ-hydroxy-α-(phenylmethyl)-2-[((fluoroalkyl)amino)carbonyl]-1-piperazinepentanamide protease inhibitors by reacting the corresponding heteroaryl carbaldehyde with the γ-hydroxy-α-(phenylmethyl)-2-[((fluoroalkyl)amino)carbonyl]-1-piperazinepentanamide penultimate in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride (see, e.g., Scheme 1 and Example 59). A drawback to the use of the cyanoborohydride or triacetoxyborohydride is their expense, particularly for large scale production. In addition, the cyanoborohydride is relatively toxic. A further example is U.S. Pat. No. 5,618,937, which discloses (see Example 4) the reductive alkylation of 2(S)-tert-butylcarboxamide piperazine with 3-pyridinecarbaldehyde in the presence of titanium tetraisopropoxide and sodium cyanoborohydride to obtain (S)-4-(3-picolyl)-2-tertbutylcarboxamide piperazine, and the subsequent heating of the alkylated piperazine (see Example 5) with the indinavir epoxide intermediate (i.e., [3aS-[3-[2(S*),3(R*)],3aα,8aα]]-3,3a,8,8a-tetrahydro-2,2-dimethyl-3-[3-(2-oxiranyl)-1-oxo-2-(phenylmethyl)propyl]-2H-indeno[1,2-d]oxazole) to give indinavir penultimate, from which the acetonide moiety was removed by treatment with HCl to provide indinavir. Drawbacks of the reductive alkylation reported in US '937 include the use of a relatively expensive and toxic reducing agent (NaBHCN3) and the relatively low yield (40%). Still another example is U.S. Pat. No. 5,508,404, which discloses the preparation of indinavir by reductive alkylation of 3-pyridinecarbaldehyde with indinavir penultimate in the presence of an excess amount of a reducing agent. The preferred reducing agents are sodium triacetoxyborohydride, sodium cyanoborohydride, and formic acid. Formic acid, however, provided a relatively low yield (43% in Example 2). Furthermore, although NaBH(OAc)3 provided a good yield (88% in Example 1), both it and NaBHCN3 are expensive reagents that would be costly to employ at least on a production scale, especially since an excess amount of the reducing agent is required to react with and remove the by-product water by formation of borate and thereby drive the equilibrium of the reaction toward the product side. US '404 also discloses that sodium borohydride can be used as a reducing agent. NaBH4 and similar tetrahydroborate salts are attractive reducing agents, because they can be effective over a wide pH range, and are inexpensive and non-toxic compared to NaBH(OAc)3 and NaBHCN3. However, US '404 does not recognize or address a significant problem posed by the use of NaBH4; i.e., the elimination of the relatively high stability amine-borane complexes that can form by reaction of borohydrides with pyridyl and other N-containing, π-deficient heteroaryls. These π-deficient heteroaryls (pyridyl, quinolinyl, isoquinolinyl, etc.) are heteroaryls that contain a ring nitrogen in an imine-type structure, the ring nitrogen having a lone pair that is not utilized in the aromatic π system. These ring nitrogens thus have a great tendency to react with electrophiles and to rapidly form unusually stable borane complexes. Conventional methods for cleaving these highly stable amine-borane complexes typically employ strong mineral acids, but these methods cannot be used with acid-sensitive compounds such as indinavir and other piperazinepentanamides of similar structure, nor can they be used with other reductively alkylated cyclic amines that contain acid-sensitive groups such as alcohols, ketones, and esters.
There is a need in the art for reductive alkylation processes that can utilize borohydride reducing agents to prepare products having π-deficient, N-containing heteraryl groups wherein the borane complexes formed during the reaction can be effectively cleaved without degradation of the final product or wherein the reaction can be conducted in such as manner as to avoid the formation of borane products altogether.
The following references are of interest as background:
Gribble et al., Organic Preparations and Procedures Int. 1985, 17 (4–5): 317–384 is a review of the properties of sodium borohydride in carboxylic acid media and the synthetic utility of acyloxyborohydrides.
Nutaltis, J. Chem. Ed. 1989, 66(8): 673–675 provides a summary of the reactions of borohydride in carboxylic acid media.
Moormann, Synth. Commun. 1993, 23(6): 789–795 discloses the reductive alkylation of piperidines with aldehydes using a borane-pyridine complex.
Abdel-Magid et al., J. Org. Chem. 1996, 61: 3849–3862 describes the reductive amination of various aldehydes and ketones with sodium triacetoxyborohyride. The reference discloses a direct amination procedure in which the amine and the aldehyde or ketone were reacted in the presence of the triacetoxyborohydride to obtain a product without the formation of an intermediate imine or iminium salt. The reference also discloses a stepwise (or indirect) procedure for use with aldehydes and primary amines that gave significant amounts of dialkylation and other side products in the direct procedure. The stepwise procedure involved reacting the aldehyde and amine in a solvent (usually methanol) to provide an aldimine intermediate, and then treating the aldimine-solvent mixture with solid NaBH4.
Couturier et al., Org. Letters 2001, 3(3): 465–467 discloses the use of palladium on carbon and Raney nickel to catalyze the methanolysis of certain borane-amine adducts.